It is widely recognized that the developing nervous system is particularly vulnerable to the effects of genetic or environmental perturbation. Indeed, several visual system disorders arise from abnormal wiring that occurs during development, and, like other neurological disorders, many are likely to have both genetic and environmental etiology. However, responses to stressors vary widely between individuals, making it difficult to associate a disease with its environmental trigger. What determines when a stressor will have catastrophic consequences to the developing embryo is poorly understood. However, in addition to regulating a variety of normal physiological processes, heat shock proteins (HSPs) buffer cells from the effects of environmental insult, such as elevated temperature, UV light, ischemia, alcohol, and heavy metal toxicity, as well as mutations in the genetic background. Therefore, defects in HSP function frequently result in increased sensitivity to environmental or genetic stressors. Small HSPs (sHSPs) are good candidates for not only protecting the developing retinal projection from stressors but also regulating normal development. The goal of this proposal is to test these possibilities using the zebrafish as a model system. The zebrafish has several advantages for analyzing the in vivo functions of candidate genes, which can be prohibitively time- and resource-intensive in other vertebrate systems. The following aims will address the function of sHSPs during development of the projection from the retina to higher visual centers: Aim I. Clone and characterize the developmental and stress-induced expression of sHSPs in zebrafish. Aim Il. Determine whether sHSPs regulate retinal ganglion cell (RGC) growth cones in vivo. Aim III. Determine whether sHSPs are required for protection and/or recovery from stressors. This will be the first systematic characterization of the embryonic functions of sHSPs, both generally and in the process of axon guidance in the visual system. The results of these studies could lead to both substantial advances in our understanding of visual system development and strategies to prevent and treat visual disorders.